This invention relates to novel sulfonyl pyridazinone compounds useful as aldose reductase inhibitors in the treatment or prevention of certain complications arising from diabetes mellitus, pharmaceutical compositions comprising the sulfonyl pyridazinone compounds, pharmaceutical compositions comprising a combination of the sulfonyl pyridazinone compounds together with a second pharmaceutical agent, therapeutic methods comprising the administration of the sulfonyl pyridazinone compounds to a mammal and therapeutic methods comprising the administration of the sulfonyl pyridazinone compounds in combination with a second pharmaceutical agent to a mammal. The invention also relates to novel compounds useful as intermediates for preparing the sulfonyl pyridazinone compounds of this invention.
The enzyme aldose reductase is involved in regulating the reduction of aldoses, such as glucose and galactose, to their corresponding polyols, such as sorbitol and galactitol. Sulfonyl pyridazinone compounds of formula I of this invention are useful as aldose reductase inhibitors in the treatment and prevention of diabetic complications of humans and other mammals associated with increased polyol levels in certain tissues (e.g., nerve, kidney, lens and retina tissue) of affected humans and other mammals.
French Patent Publication No. 2647676 discloses pyridazinone derivatives having substituted benzyl side chains and benzothiazole side chains as being inhibitors of aldose reductase.
U.S. Pat. No. 4,251,528 discloses various aromatic carbocyclic oxophthalazinyl acetic acid compounds, as possessing aldose reductase inhibitory properties.
Commonly assigned U.S. Pat. No. 4,939,140 discloses heterocyclic oxophthalazinyl acetic acid compounds.
Commonly assigned U.S. Pat. No. 4,996,204 discloses pyridopyridazinone acetic acid compounds useful as aldose reductase inhibitors.
U.S. Pat. No. 6,218,409 discloses pharmaceutical compositions comprising an insulin sensitivity enhancer in combination with one or more anti-diabetics, including aldose reductase inhibitors.
One aspect of this invention is compounds of formula I 
prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs,
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl,
with provisos that:
when X is a covalent bond, R1 is hydrogen and R2 is hydrogen, then Y is not an unsubstituted phenyl ring and Y is not a phenyl ring that is mono-substituted at the 4 position with methyl; and
when X is CHR4, R4 is H, R1 is hydrogen and R2 is hydrogen, then Y is not an unsubstituted phenyl ring.
Another aspect of this invention is pharmaceutical compositions comprising a compound of formula I 
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl, a prodrug of said compound and pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable vehicle, diluent or carrier.
An additional aspect of this invention is pharmaceutical compositions comprising a first compound of formula I 
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl,
a prodrug of said first compound and a pharmaceutically acceptable salt of said first compound or said prodrug,
and a second compound selected from:
a sorbitol dehydrogenase inhibitor;
a selective serotonin reuptake inhibitor;
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor;
an angiotensin converting enzyme inhibitor;
a glycogen phosphorylase inhibitor;
an angiotensin II receptor antagonist;
a xcex3-aminobutyric acid (GABA) agonist;
a phosphodiesterase type 5 inhibitor,
a prodrug of said second compound and a pharmaceutically acceptable salt of said second compound or said prodrug.
A further aspect of this invention is kits comprising:
a first dosage form comprising a compound of formula I 
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, 1, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, 1, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, 1, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl,
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug;
a second dosage form comprising a second compound selected from:
a sorbitol dehydrogenase inhibitor;
a selective serotonin reuptake inhibitor;
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor;
an angiotensin converting enzyme inhibitor;
a glycogen phosphorylase inhibitor;
an angiotensin II receptor antagonist;
a xcex3-aminobutyric acid (GABA) agonist;
a phosphodiesterase type 5 inhibitor,
a prodrug thereof and a pharmaceutically acceptable salt of said compound or said prodrug; and
a container.
Another aspect of this invention is therapeutic methods comprising administering to a mammal, preferably a human, in need of treatment or prevention of diabetic complications, an aldose reductase inhibiting amount of a compound of formula I 
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl,
a prodrug of said compound or a pharmaceutically acceptable salt of said compound or said prodrug.
An additional aspect of this invention is a therapeutic method comprising administering to a mammal in need of treatment or prevention of diabetic complications an aldose reductase inhibiting amount of a first compound of formula I 
wherein,
R1 and R2 are independently hydrogen or methyl,
X is a covalent bond, NR3 or CHR4, wherein,
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, and R4 is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, or
X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7,
n is independently for each occurrence 0, 1 or 2,
R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl,
a prodrug of said first compound or a pharmaceutically acceptable salt of said first compound or said prodrug, and
a second compound selected from:
a sorbitol dehydrogenase inhibitor;
a selective serotonin reuptake inhibitor;
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor;
an angiotensin converting enzyme inhibitor;
a glycogen phosphorylase inhibitor;
an angiotensin II receptor antagonist;
a xcex3-aminobutyric acid (GABA) agonist;
a phosphodiesterase type 5 inhibitor,
a prodrug of said second compound and a pharmaceutically acceptable salt of said compound or said prodrug.
In a preferred embodiment of the compound of formula I, composition and kit aspects of this invention, X is a covalent bond.
In another preferred embodiment of the compound of formula I, composition and kit aspects of this invention, X is CHR4 wherein R4 is hydrogen or methyl.
In an additional preferred embodiment of the compound of formula I, composition and kit aspects of this invention, X is NR3, wherein R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3 (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7.
In another preferred embodiment of the compound of formula I, composition and kit aspects of this invention, R1 and R2 are both hydrogen.
In a preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is a covalent bond, Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, and Oxe2x80x94(C1-C6)alkyl, wherein Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl and Oxe2x80x94(C1-C6)alkyl.
In a more preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is a covalent bond, Y is a first phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, CF3, (C1-C6)alkyl, and Oxe2x80x94(C1-C6)alkyl, wherein Ar is a second phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl and Oxe2x80x94(C1-C6)alkyl, and preferably selected from F and CF3, with the proviso that said first phenyl or naphthyl ring is substituted with no more than one Ar.
In an even more preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is a covalent bond, the compounds of formula I are preferably selected from:
6-(3-trifluoromethyl-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-bromo-2-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-trifluoromethyl-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-bromo-benzenesulfonyl)-2H-pyridazin-3-one;
6-(3,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-methoxy-benzenesulfonyl)-2H-pyridazin-3-one;
6-(3-bromo-benzenesulfonyl)-2H-pyridazin-3-one;
6-(biphenyl-4-sulfonyl)-2H-pyridazin-3-one;
6-(4xe2x80x2-fluoro-biphenyl-4-sulfonyl)-2H-pyridazin-3-one;
6-(4xe2x80x2-trifluoromethyl-biphenyl-4-sulfonyl)-2H-pyridazin-3-one;
6-(3xe2x80x2,5xe2x80x2-bis-trifluoromethyl-biphenyl-4-sulfonyl)-2H-pyridazin-3-one;
6-(biphenyl-2-sulfonyl)-2H-pyridazin-3-one;
6-(4xe2x80x2-trifluoromethyl-biphenyl-2-sulfonyl)-2H-pyridazin-3-one;
6-(2-hydroxy-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(3-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,5-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,6-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-bromo-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one; and
6-(naphthalene-1-sulfonyl)-2H-pyridazin-3-one,
more preferably from:
6-(2-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(3-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,5-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(4-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,6-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-bromo-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one; and
6-(naphthalene-1-sulfonyl)-2H-pyridazin-3-one,
even more preferably from:
6-(2-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(3-chloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,5-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,3-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,6-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-bromo-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one; and
6-(naphthalene-1-sulfonyl)-2H-pyridazin-3-one, and
especially more preferably from:
6-(2,3-difluoro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one;
6-(2-bromo-4-fluoro-benzenesulfonyl)-2H-pyridazin-3-one; and
6-(naphthalene-1-sulfonyl)-2H-pyridazin-3-one.
In a preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is CHR4 wherein R4 is hydrogen or methyl, Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, and Oxe2x80x94(C1-C6)alkyl, wherein Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3 (C1-C6)alkyl and Oxe2x80x94(C1-C8)alkyl.
In an even more preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is CHR4 wherein R4 is hydrogen or methyl, Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, CF3, (C1-C6)alkyl, and Oxe2x80x94(C1-C6)alkyl.
In an especially more preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is CHR4 wherein R4 is hydrogen or methyl, the compounds of formula I are selected from:
6-(4-bromo-2-fluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,6-dichloro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(3-chloro-5-methyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(3,4-dimethoxy-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,5-dimethoxy-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(3,5-dichloro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-methoxy-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(3,4-dimethyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(naphthalen-2-yl-methanesulfonyl)-2H-pyridazin-3-one;
6-(3,5-dichloro-2-methyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-4,6-difluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-3-methyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(4-bromo-2-fluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-fluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,4-difluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(4-chloro-2-fluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,3,4-trifluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,4,6-trifluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-fluoro-3-methyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(3-difluoromethyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,3-dichloro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-trifluoromethyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-fluoro-3-trifluoromethyl-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-chloro-6-fluoro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2-methoxy-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(2,3-dichloro-phenylmethanesulfonyl)-2H-pyridazin-3-one;
6-(1-phenyl-ethanesulfonyl)-2H-pyridazin-3-one;
6-[1-(3-trifluoromethyl-phenyl)-ethanesulfonyl]-2H-pyridazin-3-one;
6-[1-(2-trifluoromethyl-phenyl)-ethanesulfonyl]-2H-pyridazin-3-one; and
6-[1-(2,4-dichloro-phenyl)-ethanesulfonyl]-2H-pyridazin-3-one.
In a preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is NR3, wherein R3 is as defined above, Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, and Oxe2x80x94(C1-C6)alkyl, wherein Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3 (C1-C6)alkyl and Oxe2x80x94(C1-C6)alkyl.
In a more preferred embodiment of the compound of formula I, composition and kit aspects of this invention wherein X is NR3, wherein R3 is as defined above, the compound of formula I is selected from:
6-oxo-1,6-dihydro-pyridazine-3-sulfonic acid methyl-phenyl-amide;
6-oxo-1,6-dihydro-pyridazine-3-sulfonic acid isopropyl-phenyl-amide; and
6-oxo-1,6-dihydro-pyridazine-3-sulfonic acid (3,4-dichloro-phenyl)-methyl-amide.
In a preferred embodiment of the compound of formula I, composition and kit aspects of the invention, X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Ar or CH2xe2x80x94C(O)xe2x80x94Ar, R1 and R2 are both hydrogen.
In a more preferred embodiment of the compound of formula I, composition and kit aspects of the invention, X and Y together are CH2xe2x80x94CH(OH)xe2x80x94Arxe2x80x3 or CH2xe2x80x94C(O)xe2x80x94Arxe2x80x3, R1 and R2 are both hydrogen, wherein Arxe2x80x3 is 4-chlorophenyl.
In a preferred embodiment of the pharmaceutical composition, kit and therapeutic methods aspect of this invention, said compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, is of an amount effective in inhibiting the enzyme aldose reductase in a mammal, preferably a human, affected by diabetes.
In a preferred embodiment of the composition aspect of this invention wherein a composition comprises a first compound of formula I, a prodrug of said first compound or a pharmaceutically acceptable salt of said first compound or said prodrug, and a second compound, a prodrug thereof or a pharmaceutically acceptable salt of said second compound or said prodrug, the compositions further comprise a pharmaceutically acceptable vehicle, diluent or carrier.
The term xe2x80x9ccombination aspects of this inventionxe2x80x9d as used herein means, any and/or all of the following: the composition aspect of this invention wherein a composition comprises a first compound of formula I, a prodrug of said first compound or a pharmaceutically acceptable salt of said first compound or said prodrug, and a second compound, a prodrug thereof or a pharmaceutically acceptable salt of said second compound or said prodrug; the kit aspects of this invention; and, the therapeutic method aspect of this invention wherein the methods comprise administering a first compound of formula I, a prodrug of said first compound or a pharmaceutically acceptable salt of said first compound or said prodrug, and a second compound, a prodrug thereof or a pharmaceutically acceptable salt of said second compound or said prodrug.
In a preferred embodiment of the combination aspects of this invention, the second compound comprises a sorbitol dehydrogenase inhibitor, preferably in a sorbitol dehydrogenase inhibiting amount.
In a further preferred embodiment of the combination aspects of this invention, the second compound comprises a selective serotonin reuptake inhibitor, preferably in a selective serotonin reuptake inhibiting amount.
In a further preferred embodiment of the combination aspects of this invention, the second compound comprises a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, preferably in a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibiting amount.
In another preferred embodiment of the combination aspects of this invention, the second compound comprises an angiotensin converting enzyme inhibitor, preferably in an angiotensin converting enzyme inhibiting amount.
In an additional preferred embodiment of the combination aspects of this invention, the second compound comprises a glycogen phosphorylase inhibitor, preferably in a glycogen phosphorylase inhibiting amount.
In another preferred embodiment of the combination aspects of this invention, the second compound comprises an angiotensin II receptor antagonist, preferably in an angiotensin II receptor blocking amount.
In a further preferred embodiment of the combination aspects of this invention, the second compound comprises a xcex3-aminobutyric acid (GABA) agonist, preferably in a xcex3-aminobutyric acid receptor binding amount.
In an additional preferred embodiment of the combination aspects of this invention, the second compound comprises a phosphodiesterase type 5 inhibitor, preferably in a phosphodiesterase type 5 inhibiting amount
An additional aspect of this invention is compounds of formula XI 
wherein:
R1 and R2 are independently hydrogen or methyl and Z is Oxe2x80x94(C1-C6)alkyl, Oxe2x80x94Arxe2x80x2, or Oxe2x80x94CH2xe2x80x94Arxe2x80x2, wherein Arxe2x80x2 is a phenyl ring that is optionally substituted with one or more substituents selected from a halogen, a (C1-C3)alkyl and a Oxe2x80x94(C1-C3)alkyl.
In a preferred embodiment of the compound of formula XI aspects of this invention, Arxe2x80x2 is a phenyl ring that is optionally substituted with one or more substituents selected from Cl, Br and methyl and, more preferably, Arxe2x80x2 is a phenyl ring that is optionally mono- or di-substituted with Cl, Br or methyl.
In another preferred aspect of the compound of formula XI aspects of this invention R1 and R2 are both hydrogen and Z is methoxy or benzyloxy.
Another aspect of this invention is methods for preparing a compound of formula XII 
comprising reacting a compound of formula XI, as described above, with HN(R3)xe2x80x94Y to form a compound of formula XII,
wherein
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3 (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, wherein Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, n is independently for each occurrence 0, 1 or 2, R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl;
R1 and R2 are independently hydrogen or methyl; and
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, preferably (C1-C3)alkyl.
Another aspect of this invention is methods for preparing a compound of formula XIII 
comprising hydrolyzing a compound of formula XII prepared by a method of this invention with a mineral acid, preferably hydrochloric acid, to form a compound of formula XIII,
wherein:
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, wherein Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, n is independently for each occurrence 0, 1 or 2, R6 is independently for each occurrence H, (C1-C6)alkyl, phenyl or naphthyl, and
R7 is independently for each occurrence (C1-C6)alkyl, phenyl or naphthyl;
R1 and R2 are independently hydrogen or methyl; and
R3 is (C1-C3)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF3, (C1-C6)alkyl, Oxe2x80x94(C1-C6)alkyl, S(O)nxe2x80x94(C1-C6)alkyl and SO2xe2x80x94NR6R7, preferably (C1-C3)alkyl.
The expressions xe2x80x9ccompound(s) of formula Ixe2x80x9d and xe2x80x9ccompound(s) of this inventionxe2x80x9d as used herein, means a compound or compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs. The term xe2x80x9ccompound(s)xe2x80x9d when referring to compounds of formula I, also includes prodrugs of said compound(s) and pharmaceutically acceptable salts of said compound(s) or said prodrugs.
The term xe2x80x9c(C1-Ct)alkylxe2x80x9d as used herein, wherein the subscript xe2x80x9ctxe2x80x9d denotes an integer greater than 1, denotes a saturated monovalent straight or branched aliphatic hydrocarbon radical having one to t carbon atoms.
The expression xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein in relation to compounds of formula I of this invention includes pharmaceutically acceptable cationic salts. The expression xe2x80x9cpharmaceutically-acceptable cationic saltsxe2x80x9d is intended to define but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), ethanolamine, diethylamine, piperazine, triethanolamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine.
Pharmaceutically acceptable salts of the compounds of formula I of this invention may be readily prepared by reacting the free acid form of said compounds with an appropriate base, usually one equivalent, in a co-solvent. Preferred co-solvents include diethylether, diglyme and acetone. Preferred bases include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, ethanolamine, diethanolamine, piperazine and triethanolamine. The salt is isolated by concentration to dryness or by addition of a nonsolvent. In many cases, salts may be prepared by mixing a solution of the acid with a solution of a different salt of the cation (e.g., sodium or potassium ethylhexanoate, magnesium oleate) and employing a co-solvent, as described above, from which the desired cationic salt precipitates, or can be otherwise isolated by concentration.
The term xe2x80x9cprodrugxe2x80x9d denotes a compound that is converted in vivo into a compound of formula I of this invention. Such compounds include N-alkyl derivatives of formula I compounds as well as O-alkyl derivatives of formula I tautomeric compounds.
The term xe2x80x9csubstitutedxe2x80x9d when used to describe a phenyl or naphthyl ring, refers to replacement of a hydrogen atom of the phenyl or naphthyl ring with another atom or group of atoms. For example, the term xe2x80x9cmono-substitutedxe2x80x9d means that only one of the hydrogens of the phenyl or naphthyl ring has been substituted. The term xe2x80x9cdi-substitutedxe2x80x9d means that two of the hydrogens of the phenyl or naphthyl ring have been substituted.
Those skilled in the art will recognize that the compounds of this invention can exist in several tautomeric forms. All such tautomeric forms are considered as part of this invention. For example, all of the tautomeric forms of the carbonyl moiety of the compounds of formula I are included in this invention. Also, for example all enol-keto forms of compounds of formula I are included in this invention.
Those skilled in the art will also recognize that the compounds of this invention can exist in several diastereoisomeric and enantiomeric forms. All diastereoisomeric and enantiomeric forms, and racemic mixtures thereof, are included in this invention.
Those skilled in the art will further recognize that the compounds of formula I can exist in crystalline form as hydrates wherein molecules of water are incorporated within the crystal structure thereof and as solvates wherein molecules of a solvent are incorporated therein. All such hydrate and solvate forms are considered part of this invention.
This invention also includes isotopically-labeled compounds, which are identical to those described by formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
In general, the compounds of formula I of this invention may be prepared by methods that include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of formula I of this invention are illustrated by the following reaction schemes. Other processes are described in the experimental section. Some of the starting compounds for the reactions described in the schemes and Examples are prepared as illustrated herein. All other starting compounds may be obtained from general commercial sources, such as Sigma-Aldrich Corporation, St. Louis, Mo.
As shown in Scheme 1, compounds of this invention may be prepared by reacting dichloro pyridazine compounds of formula II or chloropyridazinone compounds of formula III with an alkali or alkali metal salt of Yxe2x80x94Xxe2x80x94SO2H, for example, Yxe2x80x94Xxe2x80x94SO2Na of formula IV, wherein R1, R2, X and Y are as defined herein. The reaction may be carried out in water or a mixture of water and water-miscible solvents such as dioxane or tetrahydrofuran (THF). The reaction is usually conducted at ambient pressure and at temperatures between about 80xc2x0 C. and the boiling point of the solvent used. 
Compounds of formula I may also be prepared in accordance with the steps of Scheme 2. In step 1 of Scheme 2, a compound of formula V, wherein R1, R2, X and Y are as defined herein and Z is Cl, Oxe2x80x94(C1-C6)alkyl, Oxe2x80x94Ph, Oxe2x80x94CH2xe2x80x94Ph, wherein Ph is phenyl optionally mono- or di-substituted with chlorine, bromine, or methyl, is reacted with a thiol compound of formula VI to form the formula VII sulfenyl compound. 
In one method of step 1 of Scheme 2, a formula V compound is reacted with the alkali metal salt of a formula VI thiol. The alkali metal salt is prepared by reacting the formula VI thiol with an alkali metal (C1-C6)alkoxide in (C1-C6)alkyl-OH. It is preferable that the (C1-C6)alkoxide and the (C1-C6)alkyl-OH correspond to Z of the formula V compound. For example, when Z is OMe the preferred alkoxide is an alkali metal methoxide, preferably sodium methoxide, and the preferred (C1-C6)alkyl-OH is methanol. Potassium t-butoxide may be used in any combination of alkanol and Z. Preferred metal oxides are sodium methoxide and sodium ethoxide. Excess alcohol from the reaction forming the alkali metal salt of the formula VI thiol compound is evaporated away and the resulting alkali metal salt is refluxed overnight in an aromatic hydrocarbon solvent, preferably toluene, together with the formula V compound to form the formula VII compound.
In another method of step 1 of Scheme 2, compounds of formula VII may be prepared by reacting compounds of formula V with compounds of formula VI in N,N-dimethylformamide (DMF) containing sodium or potassium carbonate. The reaction is preferably conducted at ambient pressure and at a temperature of between about 60xc2x0 C. and about 120xc2x0 C.
In a further method of step 1 of Scheme 2, compounds of formula V, wherein Z is Oxe2x80x94(C1-C6)alkyl, are reacted with compounds of formula VI either in a polar non-aqueous solvent (e.g., acetonitrile) or in an ether solvent (e.g., diglyme, tetrahydrofuran or DMF) containing alkali or alkali earth metal hydrides, preferably sodium hydride, or potassium t-butoxide. A preferred solvent is DMF.
Compounds of formula V of Scheme 2, wherein Z is Oxe2x80x94(C1-C6)alkyl, Oxe2x80x94Ph, Oxe2x80x94CH2xe2x80x94Ph, wherein Ph is phenyl optionally mono- or di-substituted with chlorine, bromine, or methyl, may be prepared by reacting a compound of formula II 
with the sodium salts of HOxe2x80x94(C1-C6)alkyl, HOxe2x80x94Ph or HOxe2x80x94CH2xe2x80x94Ph. The sodium salts may be prepared by reacting HOxe2x80x94(C1-C6)alkyl, HOxe2x80x94Ph or HOxe2x80x94CH2xe2x80x94Ph, as applicable, with sodium metal at a temperature of about 0xc2x0 C. to about 50xc2x0 C. The oxide may also be prepared by reacting HOxe2x80x94(C1-C6)alkyl, HOxe2x80x94Ph or HOxe2x80x94CH2xe2x80x94Ph with sodium hydride, optionally in the presence of a reaction-inert solvent, preferably benzene, toluene, THF or ether, at a temperature of between about 0xc2x0 C. and about room temperature.
In step 2 of Scheme 2, a compound of formula VII is oxidized to form the formula VIII sulfonyl compound. The formula VII compounds may be oxidized with 30% hydrogen peroxide, optionally in the presence of formic acid, acetic acid or a peracid, such as m-chloroperbenzoic acid (MCPBA), in a halocarbon solvent (e.g., dichloromethane). The reaction is preferably conducted at ambient pressure and at a temperature of between about 20xc2x0 C. and about 40xc2x0 C., and is complete in about three to about six hours. The reaction should be monitored carefully to avoid over-oxidation of the nitrogen atoms to N-oxides. N-oxides that are formed may be converted to the reduced pyridazine compound by reacting the N-oxide with triethylphosphite, sodium sulfite or potassium sulfite, preferably at about 100xc2x0 C. for about four hours.
The formula VIII compounds of step 3 of Scheme 2 are hydrolyzed with a mineral acid, e.g., concentrated hydrochloric acid, alone or in an ether solvents such as dioxane, to obtain the compound of formula I. The reaction of step 3 is preferably conducted at ambient pressure and at the refluxing temperature of the solvent used.
Scheme 3 provides still another method of preparing compounds of formula I. In Scheme 3, a chloropyridazinone compound of formula III is reacted with a thiol compound of formula VI to form a sulfinylpyridazinone compound of formula XI. The reaction is preferably performed in the presence of an alkali or an alkali metal alkoxide, for example potassium tertbutoxide, in reaction-inert polar solvent such as DMF or acetonitrile at about room temperature to about 100xc2x0 C. The resulting compound of formula I is oxidized with hydrogen peroxide, optionally in the presence of acetic acid or a peracid, preferably m-chloroperbenzoic acid (MCPBA), in a halocarbon solvent such as dichloromethane, to form the compound of formula I. 
Compounds of formula I wherein X is CHR4, wherein R4 is hydrogen or methyl may be prepared according to Scheme 4. In step 1 of Scheme 4, a compound of formula X, wherein Z is Cl, Oxe2x80x94(C1-C6)alkyl, Oxe2x80x94Ph1, Oxe2x80x94CH2xe2x80x94Ph1, wherein Ph1 is phenyl optionally mono- or di-substituted with chlorine, bromine, or methyl, is reacted with Yxe2x80x94Xxe2x80x94L, wherein L is a leaving group, preferably Cl, Br, I, OSO2CH3, OSO2CF3, or OSO2Ph2, wherein Ph2 is a phenyl optionally monosubtituted with Br, Cl or OCH3, in the presence of a base, preferably sodium carbonate, potassium carbonate or sodium hydride to form a compound of formula VII. When the base is sodium carbonate or potassium carbonate, the reaction solvent is preferably acetone. However, if the base is sodium hydride, DMF or acetonitrile is used as the reaction solvent. The reaction is preferably conducted at ambient pressure and at a temperature of between about room temperature and about 100xc2x0 C. Steps 2 and 3 are analogous to steps 2 and 3 of Scheme 2 and are conducted in the same manner thereof. 
Compounds of formula I wherein X and Y together form CH2C(O)Ar may be prepared according to Scheme 4 by reacting, in step 1, compounds of formula X with LCH2C(O)Ar to form a compound of formula VII The reaction is conducted in the presence of a base, preferably sodium carbonate or potassium carbonate and in a reaction-inert solvent such as dimethyl formamide. The reaction temperature is preferably from about room temperature to about 80xc2x0 C. Steps 2 and step 3 of Scheme 4 are performed in a manner analogous to steps 2 and 3 of Scheme 2.
Compounds of formula I wherein X and Y together form xe2x80x94CH2CH(OH)Ar may be prepared by reacting compounds of formula I wherein X and Y together form xe2x80x94CH2C(O)Ar with sodium borohydride in alcoholic solvents such as methanol, ethanol or isopropanol. The reaction is preferably conducted at a temperature of about 0xc2x0 C. to about 60xc2x0 C. and at ambient pressure.
Compounds of formula I wherein X is NF3 wherein R3 is (C1-C3)alkyl (formula XIII compounds) may be prepared in accordance with Scheme 5. In step 1 of Scheme 5, a compound of formula V, wherein Z is Cl, xe2x80x94Oxe2x80x94(C1-C6)alkyl, Oxe2x80x94Ph, Oxe2x80x94CH2xe2x80x94Ph, wherein Ph is phenyl optionally mono- or di-substituted with chlorine, bromine, or methyl, is reacted with thiourea in a ketone solvents, preferably acetone, ethyl methyl ketone or isobutyl ketone, to obtain a compound of formula X. Step 1 is conducted at ambient pressure and at the refluxing temperature of the solvent. Compounds of formula V may be prepared as described above for Scheme 2. 
In step 2 of Scheme 5, a compound of formula XI is prepared according to the process disclosed in J. Heterocyclic Chem., 1998, 35, 429-436. Compounds of formula XI are particularly useful as intermediates in the preparation of compounds of formula I.
In Step 3 of Scheme 5, a formula XII compound is prepared by reacting a compound of formula XI with excess HN(R3)xe2x80x94Y, optionally in an organic reaction inert base, preferably a trialkyl amine selected from trimethylamine, triethylamine, and dimethyl-isopropyl-amines, more preferably triethylamine. The reaction may optionally be performed in a reaction inert solvent such as an ether, halocarbon or aromatic hydrocarbon solvent, preferably selected from diethyl ether, isopropyl ether, tetrahydrofuran, diglyme, chloroform, methylene dichloride, benzene and toluene. The reaction of step 3 is preferably performed at a temperature of about room temperature to about the refluxing temperature of the solvent that is used.
In step 4 of Scheme 5, a compound of formula XIII may be prepared by hydrolyzing a compound of formula XII with a mineral acid such as concentrated hydrochloric acid, either alone or an ether solvent (e.g., dioxane). The reaction may be conducted at about room pressure to about the refluxing temperature of the solvent used.
Compounds of formula I wherein X is a covalent bond and Y is a phenyl or napthyl ring substituted with hydroxy may be prepared by reacting compounds of formula I wherein Y is phenyl or naphthyl substituted with C1-C6 alkoxy with a dealkylating reagents such as AlCl3, AlBr3, or BF3. When AlCl3 or AlBr3 are the dealkylating reagent, the reaction is preferably carried out without any solvent. When the dealkylating reagent is BF3, a halocarbon solvent is preferably used, preferably methylene chloride or ethylene chloride. The reaction is conducted at ambient pressure and at temperatures between about xe2x88x9260xc2x0 C. to about 80xc2x0 C.
Compounds of formula I wherein X is a covalent bond and Y is phenyl or naphthyl substituted with an optionally substituted phenyl or naphthyl ring may be prepared by first reacting compounds of formula VIII wherein X is a covalent bond, Z is Oxe2x80x94(C1-C6)alkyl, Y is a phenyl or napthyl that has a bromo or iodo substitutent with an appropriately substituted phenyl or naphthyl boronic acid in the presence of a palladium catalyst such as Pd[P(Ph)3]4 and in the presence of either potassium carbonate or sodium carbonate. The reaction is preferably conducted in an aromatic hydrocarbon solvent, preferably toluene, or in a C1-C6 alcohol, preferably ethanol, at ambient pressure and at a temperature of about room temperature to the refluxing temperature of the solvent used. The product of the first step is hydrolyzed with a mineral acid, preferably hydrochloric acid, alone or an ether solvent, preferably dioxane, to obtain a compound of formula I wherein Y is phenyl or naphthyl substituted with an optionally substituted phenyl or naphthyl ring.
The compounds of formula I of the present invention inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase and as such have utility in the treatment of diabetic complications including but not limited to such complications as diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic cataracts and tissue ischemia. Such aldose reductase inhibition is readily determined by those skilled in the art according to standard assays known to those skilled in the art (e.g., B. L. Mylari, et al., J. Med. Chem., 1991, 34, 108-122) and according to the protocol described in the General Experimental Procedures.
This invention also relates to therapeutic methods for treating or preventing diabetic complications in a mammal wherein a compound of formula I of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula I of this invention being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions. Generally, in carrying out the methods of this invention, an effective dosage for the compounds of formula I of this invention is in the range of about 0.1 mg/kg/day to about 500 mg/kg/day in single or divided doses. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
The standard assays used to determine aldose reductase inhibiting activity, as described above, may be used to determine dosage levels in humans and other mammals of the compounds of formula I of this invention. Such assays provide a means to compare the activities of the compounds of formula I of this invention and other known compounds that are aldose reductase inhibitors. The results of these comparisons are useful for determining such dosage levels.
The term xe2x80x9cSecond Agentsxe2x80x9d hereinafter refers collectively to pharmaceutical compounds or agents that are sorbitol dehydrogenase inhibitors, selective serotonin reuptake inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, angiotensin converting enzyme inhibitors, glycogen phosphorylase inhibitors, angiotensin II receptor antagonists, xcex3-aminobutyric acid agonist, phosphodiesterase type 5 inhibitors, a prodrug of said compounds or agents, or a pharmaceutically acceptable salt of such compound, agent or prodrug. Use of the term in singular form, as in xe2x80x9ca Second Agentxe2x80x9d hereinafter refers to a pharmaceutical agent selected from said Second Agents. A Second Agent may be a pharmaceutical agent that shares more than one of the foregoing characteristics.
An additional aspect of this invention relates to pharmaceutical compositions comprising a compound of formula I of this invention, and a Second Agent. Such compositions are hereinafter referred to collectively as the xe2x80x9ccombination compositionsxe2x80x9d.
This invention also relates to therapeutic methods for treating or preventing diabetic complications in a mammal wherein a compound of formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition or separately. Such methods are hereinafter referred to collectively as the xe2x80x9ccombination therapiesxe2x80x9d of this invention. Combination therapies include therapeutic methods wherein a compound of formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition and to methods wherein these two agents are administered separately, either simultaneously or sequentially in any order.
This invention further provides pharmaceutical kits comprising a compound of formula I of this invention and a Second Agent. Such kits may hereinafter be referred to as the xe2x80x9ckitsxe2x80x9d of this invention.
Any selective serotonin reuptake inhibitor (SSRI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term selective serotonin reuptake inhibitor refers to an agent which inhibits the reuptake of serotonin by afferent neurons. Such inhibition is readily determined by those skilled in the art according to standard assays such as those disclosed in U.S. Pat. No. 4,536,518 and other U.S. patents recited in the next paragraph.
Preferred selective serotonin reuptake inhibitors which may be used in accordance with this invention include femoxetine, which may be prepared as described in U.S. Pat. No. 3,912,743; fluoxetine, which may be prepared as described in U.S. Pat. No. 4,314,081; fluvoxamine, which may be prepared as described in U.S. Pat. No. 4,085,225; indalpine, which may be prepared as described in U.S. Pat. No. 4,064,255; indeloxazine, which may be prepared as described in U.S. Pat. No. 4,109,088; milnacipran, which may be prepared as described in U.S. Pat. No. 4,478,836; paroxetine, which may be prepared as described in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sertraline, which may be prepared as described in U.S. Pat. No. 4,536,518; sibutramine, which may be prepared as described in U.S. Pat. No. 4,929,629; and zimeldine, which may be prepared as described in U.S. Pat. No. 3,928,369. Fluoxetine is also known as Prozac(copyright). Sertraline hydrochloride is also known as Zoloft(copyright). Sibutramine is also known as Meridia(copyright). The disclosures thereof are incorporated herein by reference.
Selective serotonin reuptake inhibitors are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the selective serotonin reuptake inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor refers to a pharmaceutical agent which inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is involved in the conversion of HMG-CoA to mevalonate, which is one of the steps in cholesterol biosynthesis. Such inhibition is readily determined according to standard assays well known to those skilled in the art.
Preferred 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors which may be used in accordance with this invention include atorvastatin, disclosed in U.S. Pat. No. 4,681,893, atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, cerivastatin, disclosed in U.S. Pat. No. 5,502,199, dalvastatin, disclosed in European Patent Application Publication No. 738,510 A2, fluindostatin, disclosed in European Patent Application Publication No. 363,934 A1, fluvastatin, disclosed in U.S. Pat. No. 4,739,073, lovastatin, disclosed in U.S. Pat. No. 4,231,938, mevastatin, disclosed in U.S. Pat. No. 3,983,140, pravastatin, disclosed in U.S. Pat. No. 4,346,227, simvastatin, disclosed in U.S. Pat. No. 4,444,784 and velostatin, disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171, all of which are incorporated herein by reference. Especially preferred 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors include atorvastatin, atorvastatin calcium, also known as Liptor(copyright), lovastatin, also known as Mevacor(copyright), pravastatin, also known as Pravachol(copyright), and simvastatin, also known as Zocor(copyright).
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are preferably administered in amounts ranging from about 0.1 mg/kg to about 1000 mg/kg/day in single or divided doses, preferably about 1 mg/kg/day to about 200 mg/kg/day for an average subject, depending upon the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any angiotensin converting enzyme (ACE) inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term angiotensin converting enzyme inhibitor refers to a pharmaceutical agent which inhibits angiotensin converting enzyme activity. Angiotensin converting enzyme is involved in the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The activity of angiotensin converting enzyme inhibitors may readily be determined by methods known to those skilled in the art, including any of the standard assays described in the patents listed below.
Preferred angiotensin converting enzyme inhibitors include: alacepril, disclosed in U.S. Pat. No. 4,248,883; benazepril, disclosed in U.S. Pat. No. 4,410,520; captopril, disclosed in U.S. Pat. Nos. 4,046,889 and 4,105,776; ceronapril, disclosed in U.S. Pat. No. 4,452,790; delapril, disclosed in U.S. Pat. No. 4,385,051; enalapril, disclosed in U.S. Pat. No. 4,374,829; fosinopril, disclosed in U.S. Pat. No. 4,337,201; imadapril, disclosed in U.S. Pat. No. 4,508,727; lisinopril, disclosed in U.S. Pat. No. 4,555,502; moexipril, disclosed in U.S. Pat. No. 4,344,949; moveltopril, disclosed in Belgian Patent No. 893,553; perindopril, disclosed in U.S. Pat. No. 4,508,729; quinapril, disclosed in U.S. Pat. No. 4,344,949; ramipril, disclosed in U.S. Pat. No. 4,587,258; spirapril, disclosed in U.S. Pat. No. 4,470,972; temocapril, disclosed in U.S. Pat. No. 4,699,905; and trandolapril, disclosed in U.S. Pat. No. 4,933,361. The disclosures of all such patents are incorporated herein by reference.
Angiotensin converting enzyme inhibitors are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the angiotensin converting enzyme inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any angiotensin-II receptor (A-II), antagonist may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term angiotensin-II receptor antagonist refers to a pharmaceutical agent that blocks the vasoconstrictor effects of angiotensin II by blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). The activity of angiotensin-II receptor antagonist may readily be determined by methods known to those skilled in the art, including any of the standard assays described in the patents listed below.
Preferred angiotensin-II receptor antagonists include: candesartan, which may be prepared as disclosed in U.S. Pat. No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat. No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S. Pat. No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Pat. No. 5,138,069; and valsartan, which may be prepared as disclosed in U.S. Pat. No. 5,399,578. The disclosures thereof are incorporated herein by reference. More preferred angiotensin-II receptor antagonists are losartan, irbesartan and valsartan.
Angiotensin-II receptor antagonists are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the angiotensin-II receptor antagonist and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any xcex3-aminobutyric acid (GABA) agonist may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term xcex3-aminobutyric acid agonist refers to a pharmaceutical agent that binds to GABA receptors in the mammalian central nervous system. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. The activity of xcex3-aminobutyric acid (GABA) agonist may readily be determined by methods known to those skilled in the art, including the procedures disclosed in Janssens de Verebeke, P. et al., Biochem. Pharmacol., 31, 2257-2261 (1982), Loscher, W., Biochem. Pharmacol., 31, 837-842, (1982) and/or Phillips, N. et al., Biochem. Pharmacol., 31, 2257-2261.
Preferred xcex3-aminobutyric acid agonist include: muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin(copyright)), vigabatrin, valproic acid, tiagabine (Gabitril(copyright)), lamotrigine (Lamictal(copyright)), pregabalin, phenytoin (Dilantin(copyright)), carbamazepine (Tegretol(copyright)), topiramate (Topamax(copyright)) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of those xcex3-aminobutyric acid agonist agonists.
In general, in accordance with this invention, the xcex3-aminobutyric acid agonist used in the combinations, pharmaceutical compositions, methods and kits of this invention will be administered in a dosage amount of about 4 mg/kg body weight of the subject to be treated per day to about 60 mg/kg body weight of the subject to be treated per day, in single or divided doses. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. In particular, when used as they-aminobutyric acid agonist agonist in this invention, pregabalin will be dosed at about 300 mg to about 1200 mg per day; gabapentin will be dosed at about 600 mg to about 3600 mg per day.
Any glycogen phosphorylase inhibitor (GPI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of glycogen phosphorylase. Such actions are readily determined by those skilled in the art according to standard assays as described in U.S. Pat. No. 5,988,463.
U.S. Pat. No. 5,988,463, PCT application publication WO 96/39384 and PCT application publication WO96/39385 exemplify glycogen phosphorylase inhibitors which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those glycogen phosphorylase inhibitors.
Glycogen phosphorylase inhibitors are preferably administered in amounts ranging from about 0.005 mg/kg/day to about 50 mg/kg/day in single or divided doses, preferably about 0.1 mg/kg to about 15 mg/kg per day for an average subject, depending upon the glycogen phosphorylase inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any sorbitol dehydrogenase inhibitor (SDI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term sorbitol dehydrogenase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of sorbitol dehydrogenase. Sorbitol dehydrogenase is believed to catalyze the oxidation of sorbitol to fructose.
Sorbitol dehydrogenase inhibitors are disclosed in commonly assigned U.S. Pat. No. 5,728,704, U.S. Pat. No. 5,866,578 and PCT application publication WO 00/59510, incorporated herein by reference.
The activity of sorbitol dehydrogenase inhibitors may be evaluated using the assays and methods disclosed in commonly assigned PCT application publication WO 00/59510 and other assays and methods known by those skilled in the art.
Sorbitol dehydrogenase inhibitors are preferably administered in amounts ranging from about 0.001 mg/kg/day to about 100 mg/kg/day in single or divided doses, preferably about 0.01 mg/kg to about 10 mg/kg per day for an average subject, depending upon the sorbitol dehydrogenase inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
Any phosphodiesterase type 5 (PDE-5) inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term phosphodiesterase type 5 inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5. Such actions are readily determined by those skilled in the art according to assays as described in PCT application publication WO 00/24745.
The following patent publications exemplify phosphodiesterase type 5 inhibitors which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those phosphodiesterase type 5 (PDE-5) inhibitors: PCT application publication WO 00/24745; PCT application publication WO 94/28902; European Patent application publication 0463756A1; European Patent application publication 0526004A1 and European Patent application publication 0201188A2. A preferred phosphodiesterase type 5 inhibitor is sildenafil citrate, also known as Viagra(copyright).
Phosphodiesterase type 5 inhibitors are preferably administered in amounts ranging from about 5 mg/day to about 500 mg/day in single or divided doses, preferably about 10 mg/day to about 250 mg/day, for an average subject depending upon the phosphodiesterase type 5 inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
In the aspects of this invention related to therapeutic methods of treating or preventing diabetic complications wherein a compound of formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition and to methods wherein these two agents are administered separately, the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the active agents will again depend upon the compound of formula I of this invention and the Second Agent being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions.
Administration of the compounds and pharmaceutical compositions of this invention may be performed via any method which delivers a compound or composition of this invention preferentially to the desired tissue (e.g., nerve, kidney, lens, retina and/or cardiac tissues). These methods include oral routes, parenteral, intraduodenal routes, etc, and may be administered in single (e.g., once daily) or multiple doses or via constant infusion.
The pharmaceutical compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository or using a xe2x80x9cflashxe2x80x9d formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
The compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia. Additionally, lubricating agents such as magnesium stearate, sodium laurylsulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
For parenteral administration, solutions of the compounds of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Generally, a composition of this invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
Buccal administration of a composition of this invention may take the form of tablets or lozenges formulated in a conventional manner.
For intranasal administration or administration by inhalation, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of a compound of this invention. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
In the aspects of this invention related to the combination compositions, wherein the compositions contain an amount of both a compound of formula I of this invention, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug and a Second Agent, the amount of each such ingredient may independently be, 0.0001%-95% of the total amount of the composition, provided, of course, that the total amount does not exceed 100%. In any event, the composition or formulation to be administered will contain a quantity of each of the components of the composition according to the invention in an amount effective to treat the disease/condition of the subject being treated.
Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a first pharmaceutical composition comprising a compound of formula I of this invention, a prodrug thereof or a pharmaceutically acceptable salt of such compound or prodrug; and a second pharmaceutical composition comprising a agent selected from a sorbitol dehydrogenase inhibitor, a selective serotonin reuptake inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, an angiotensin converting enzyme inhibitor, a glycogen phosphorylase inhibitor, a angiotensin II receptor antagonist, a xcex3-aminobutyric acid agonist or a phosphodiesterase type 5 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said second agent or prodrug as described above. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc . . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several tablets or capsules to be taken on a given day. Also, a daily dose of a compound of this invention can consist of one tablet or capsule while a daily dose of the Second Agent can consist of several tablets or capsules, or vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The journal articles and scientific references, patents and patent application publications cited above are wholly incorporated herein by reference.
Melting points were determined on a Thomas-Hoover capillary melting point apparatus, and are uncorrected. 1H NMR spectra were obtained on a Bruker AM-250 (Bruker Co., Billerica, Mass.), a Bruker AM-300, a Varian XL-300 (Varian Co., Palo Alto, Calif.), or a Varian Unity 400 at about 23xc2x0 C. at 250, 300, or 400 MHz for proton. Chemical shifts are reported in parts per million (6) relative to residual chloroform (7.26 ppm), dimethylsulfoxide (2.49 ppm), or methanol (3.30 ppm) as an internal reference. The peak shapes and descriptors for the peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; c, complex; br, broad; app, apparent. Low-resolution mass spectra were obtained under thermospray (TS) conditions on a Fisons (now Micromass) Trio 1000 Mass Spectrometer (Micromass Inc., Beverly, Mass.), under chemical-ionization (Cl) conditions on a Hewlett Packard 5989A Particle Beam Mass Spectrometer (Hewlett Packard Co., Palo Alto, Calif.), or under atmospheric pressure chemical ionization (APCI) on a Fisons (now Micromass) Platform II Spectrometer.